Several genes have recently been described that are involved with insulin secretion and action. For example, mutations in genes which play a role in insulin secretion (namely HNF 4a, glucokinase and HNF 1a) have been identified as the genetic defects underlying MODY 1, MODY 2, and MODY 3. We analyzed the HNF 1a gene for mutations which could give rise to the early onset of NIDDM in Pimas. We selected 20 Pimas with an onset of NIDDM before the age of 20, and analyzed the coding region and promoter region of the HNF 1a gene for sequence variability. One novel silent polymorphism was identified in a "mutational hotspot" within the gene, but this polymorphism was not associated with early onset diabetes. Consequently we conclude that mutations in HNF 1a do not play a major role in the development of early onset NIDDM in the Pimas. We have also investigated candidate genes in an area of linkage on chromosome 1. The genes which encode the retinoid X receptor gamma, pyruvate kinase, the insulin promoter binding factor LMX, and Apo A2 have been mapped to a chromosomal region potentially linked to NIDDM, the mean glucose level during an IVGTT, glucose disposal as measured by a hyperinsulinemic, euglycemic clamp, and 24-hour energy expenditure. No polymorphisms were detected in the coding regions of the retinoid X receptor gamma gene nor the pyruvate kinase gene. We are currently investigating the sequence of the genes for LMX and Apo A2.